Though combinations of cytotoxic drugs are routinely administered to cancer patients in the clinic, nanoparticle (NP)-based combination therapy still represents an emerging frontier in cancer drug delivery. Effective combination therapies are particularly necessary for ovarian cancer, as ovarian cancer cells often display resistance to current clinical therapies such as platinum agents (cisplatin), paclitaxel, and PARP inhibitors (PARPi), and systemic administration of these drugs in free from is precluded by extreme toxicity. Furthermore, platinum and PARPi resistance is a major challenge in ovarian cancer therapy. NPs have the potential to reduce the toxicity of chemotherapy, and they could maximize efficacy and overcome resistance through rational drug choices that target several disparate DNA repair pathways simultaneously. In order to determine if a particular drug combination is working, microenvironment-responsive imaging strategies that are clinically translatable (e.g., MRI) are critically needed. The PI?s group has developed novel organic polymer NPs with demonstrated advantages in combination ovarian cancer therapy as well as MRI. These studies inspired our proposed NPs, which combine responsive organic MRI handles and rational drug combinations for image- guided selection of optimal therapies for ovarian cancer. The proposed research combines a novel drug-NP and imaging agent synthesis (from Johnson and Rajca) with clinical expertise in ovarian cancer (Ghoroghchian) and biomedical imaging (Jasanoff) and fundamental cancer biology and targeting (Kufe lab) to address chemoresistance in ovarian cancer through novel image-guided NP-based combination therapies. The proposed research will create a new paradigm for ovarian cancer therapy, whereby combinations of several therapeutic agents are packaged within the same non-toxic carrier and delivered selectively to tumors and MRI contrast agents within the nanomaterial report on the success of the therapy, thus allowing one to select an optimum drug combination and ratio for personalized therapy. HYPOTHESIS: Simultaneous incorporation of multiple small-molecule therapeutic agents and responsive imaging tags (MRI) into multi-drug-conjugated NPs will lead to novel therapies for ovarian cancer that delay the development of acquired therapeutic resistance and provide for MRI-guided drug selection. In combination with other established and experimental agents, one or more NPs will be established with improved activity in platinum-resistant disease. The already proven safety, pharmacokinetics, biodistribution, and efficacy of 3-drug containing NPs for high-grade serous ovarian cancer therapy will translate to novel drug combinations that are effective in vivo, as will be demonstrated by activity in orthotopic patient-derived xenograft models of Pt- and PARPi-resistant ovarian cancer. Inclusion of multiple drugs in one NP will lead to increased efficacy and decreased toxicity compared to mixtures of single-drug-conjugated NPs and free drugs at the same ratios. The development of entirely organic MRI contrast agents will ensure safety and clinical translatability.